BRPI0614097A2 - multiple chamber container - Google Patents

Abstract

A multiple chamber container for separately storing components of a parenteral nutritional formulation is provided. The multiple chamber container may include frangible barriers, preferably peelable seals separating the chambers from each other. The container preferably facilitates the selective activation of the peelable seals to permit the admixing of less than all the separately stored components. The container may include a chamber positioned at each of the opposite lateral ends of the container and at least one additional chamber between the lateral chambers. The at least one additional chamber may have a longitudinal length substantially less than the longitudinal length of at least one of the lateral chambers. This configuration allows for selective opening of the seals since when rolling the container from the top avoids pressurizing the at least one additional chamber and inadvertent activation of a seal. The longitudinal length of the at least one additional chamber may be from about two-thirds to about three-fourths the longitudinal length of at least one of the lateral chambers. Alternatively, the container may include a hanger flap extending from a top end of the container towards the bottom end a substantially greater distance relative to the at least one additional chamber than the lateral chambers.

Description

Descriptive Report of the Invention Patent for "MULTIPLE CAMERA CONTAINER".

This patent application claims the benefit of U.S. Provisional Application Serial Number 60 / 704,555, filed August 2, 2005.

BACKGROUND OF THE INVENTION

The present invention generally relates to medical solutions, containers for storing medical solutions, and oxygen indicators for detecting the presence of oxygen in a medical container. More particularly, the present invention relates to ready-to-use, ternary, parenteral nutrition formulations for certain patient populations, particularly fluid-limited populations, to food storage container systems. long-term and selective administration of these formulations, and to oxygen indicators for these container systems.

More specifically, the present invention relates to the storage of such formulations in flexible multi-chamber containers for long-term storage isolated from the various nutritional components of such formulations, to oxygen indicators to alert healthcare professionals of the compromise of oxygen in a container and containers facilitate sterile, selective mixing for a forward formulation for infusion and administration of such formulation. Even more specifically, the invention relates to multi-chamber containers, which permit the selective mixing of two or more solutions contained in the chambers, such as lipid, carbohydrate, amino acid and electrolyte nutrient solutions and oxygen indicators capable of resist thermal sterilization and with acceptable storage characteristics.

Medical solutions, such as nutrition, parenteral and enteral solutions, dialysis solutions, pharmacological solutions, and chemotherapeutic solutions, are routinely stored in a multitude of containers made of glass or plastic. Although glass containers offer many benefits, such as gas tightness and virtually complete compatibility with medical solutions, glass containers are heavy, easily breakable, difficult to handle and can release aluminum solutions. As a result, more and more medical solutions are being stored in plastic containers. Flexible containers, such as plastic film bags, have been increasingly accepted.

Often, the revenue to be administered to a patient consists of components that are not all compatible for long storage periods. A physician to overcome this limitation is to combine or mix the components just prior to administration. This mixing can be performed manually or with automatic mixers. But this combination method takes time, can lead to errors in formulation and increases the risks of contamination of the final mix.

To overcome the disadvantages of long term incompatibility and reduce the risks of mixing, flexible containers can be formed with multiple chambers to store medium solutions separately.

These pouches are formed with frangible joints or detachable seals, which enable the mixing of all chamber contents by manipulation of the joints or seals. A disadvantage of using such multiple chamber containers is that it is limited to the formulation that is produced by the components offered and proportional amounts that are housed in the various chambers. When seeking to meet the needs of variable patient populations, particularly fluid-limited populations, this limitation may impede the ability to use these containers, cause only a portion of the contents of these containers to be used, or cause multiple versions of these containers to be stored. .

As previously described, flexible multi-chamber containers, such as multi-chamber pockets, have separation means for communicating and mixing separately stored components or solutions. Some of these multi-bed containers utilize frangible valves, while others use a notched or weakening line in the barrier separating the chambers to mix separately stored components. Still others use tear strips or tear tabs. Most cost-effective and easy-to-use chamber containers are of the type that include detachable seals formed by thermal sealing or radiofrequency of the two sheets of thermoplastic material, which constitute a flexible pouch, to define multiple inner chambers. The thermal seal creates a barrier that is resistant to unintended opening forces, but can be broken with the application of a specific force. Such types of multiple chamber containers are described in U.S. 6,319,243, which is incorporated herein by reference.

Plastic containers such as those described above may, however, also have unique aspects which need to be resolved. One possible aspect is that thermal sterilization, such as autoclaving, may affect certain plastic materials used to form the container and / or the thermal seal that separates the chambers. Another aspect is that certain plastic materials are permeable to atmospheric oxygen and may inappropriately protect oxygen-sensitive solutions or components. Yet another aspect is that certain fat soluble or lipophilic solutions or components may not be compatible with certain plastic materials. For example, delipid formulations, such as lipid emulsions used in parenteral nutrition, cannot be stored in certain plastics because they may contain some plastic material from the container. Lipid emulsion would be contaminated and the integrity of the plastic containers could be compromised.

Lipid boosts are usually a component of a parenteral nutrition (PN) solution. Ternary parenteral nutrition formulations are used to provide all the necessary nutritional components to the patient. These PN formulations also include a carbohydrate component, an amino acid component, vitamin, trace elements, and electrolyte components. Due to various incompatibilities, the nutritive components of PN formulations are prime examples of medical breakdowns that cannot be stored long term with the mixture in a ready-to-use state. They can only be combined within a relatively short period of time before administration. The individual constituents of each component should be determined by the recommended nutrition needs for a specific patient population to be treated. For example, PN formulations for adult patients may have different constituents in each component or at least different amounts of each constituent than infant PN formulations. Furthermore, the preparation of separate components of PN formulations for premature infants, neonatal patients or young children presents specific problems. On the one hand, the volume of fluid that can be infused in these patients is relatively small. Trying to provide all the desired nutritional components in this small volume is extremely difficult. For example, the concentration limits for individual constituents of particular component solutions need to be narrowly restricted. In addition, some of the individual constituents are interdependent or incompatible when present in certain forms and concentrations. For example, the acceptable magnesium concentration range for a premature baby is about 0.2 mmol. In other words, the difference between the lowest acceptable magnesium concentration and the highest acceptable magnesium concentration is 0.2 mmol. In addition, there is a limit to the amount of chlorine that a premature baby can tolerate; Thus, in an attempt to provide the required amount of certain electrolytes, such as magnesium and calcium as a chloride, the maximum chloride may be exceeded.

In addition, electrolytes such as calcium and phosphate may be incompatible at certain concentration levels.

Also, storing the components of a PN formulation in a single or multiple chamber plastic container for sterile mixing to form the PN formulation also presents specific problems. As already described above, the lipid component is compatible with certain plastic materials. In addition, some of the components are oxygen sensitive, which can permeate through certain plastics. Outer wraps or outer pouches are typically used to limit the ability of oxygen to reach multiple chamber containers; but the outer wrap may still allow a small amount of oxygen to be permeated therethrough. In addition, the outer wrapper could create a leak, which would allow an excessive amount of oxygen to be exposed to the container. This leak may not be visible and the presence of this oxygen needs to be indicated to the healthcare professional. Although there are oxygen indicators, it appears that they are not able to withstand thermal sterilization and still function properly after prolonged storage. In other words, the oxygen indicator must be able to indicate the presence of oxygen (is oxidized form or positive result), such as decor change, that is distinguishable from the state that indicates the absence of oxygen (reduced form or negative result). In addition, the indicator's faded oxidized colors should not fade or change after prolonged storage to create uncertainty as to the result.

In addition, certain thiol-functional amino acids, such as cysteine or acetyl cysteine, may form hydrogen sulfide as a decomposition product during sterilization. Excessive hydrogen sulfide level may negatively affect some of the nourishing components. In addition, although all separately stored components are mixed to form the final PN formulation prior to administration, there are circumstances in which it is undesirable to include one or more of the components found in one of the chambers in the final solution. For example, it may be desirable not to include the lipid component in the final solution for septic infants, coagulation abnormalities, bilirubin elevation level or for other reasons.

There is therefore a need for a flexible multi-chamber container that facilitates the selective opening of one but the other frangible barrier, less than all frangible barriers or frangible barriers sequentially.

There is also a need for individual components of an N formulation that meet the recommended volume and nutrition requirements for particular patient populations and particularly infants or young children at different stages of development.

In addition, there is a need for means to provide a reliable indication that atmospheric oxygen may have contaminated the contents of the container, a low level of hydrogen sulfide, in the case of formulation containing cysteine or derived amino acids and an oxygen absorber, to eliminate residual oxygen in the outer bag. It would be desirable to obtain absorbers and / or indicators that can resist thermal sterilization and prolonged storage and still have the ability to indicate that an unacceptable amount of oxygen has been exposed to the container.

SUMMARY OF THE INVENTION

In a first aspect of the present invention, there is provided a flexible container for storing medical products. The flexible container comprises a plurality of adjacent chambers, a first chamber positioned at one side end of the container, a second chamber positioned at an opposite side end of the container. camera and at least one additional camera positioned between the first and second cameras; a first frangible barrier separating the first chamber from at least one additional chamber, and a second frangible barrier separating the second chamber from at least one additional chamber; at least two openings located at one end of the container; each aperture provides fluid communication with a chamber other than the first and second chambers and at least one additional chamber, wherein a longitudinal length of the at least one further chamber is substantially less than at least one of the longitudinal lengths of the first and second chambers. of the second chamber.

The flexible container described in the first aspect of the present invention, wherein the longitudinal length of at least one additional chamber may be substantially smaller than the longitudinal length of both the first and second chambers.

The flexible container described in the first aspect of the present invention, wherein the longitudinal length of one of the first and second chambers may be substantially shorter than the longitudinal length of at least one additional chamber.

The flexible container described in the first aspect of the present invention, wherein the longitudinal length of one of the first and second chambers may be equal to the longitudinal length of at least one additional chamber.

The flexible container described in the first aspect of the present invention, wherein the container may be in the form of a pouch and may consist of a multilayer polymeric material.

The flexible container described in the first aspect of the present invention the first and second barriers may be peelable seals.

The flexible container described in the first aspect of the present invention may further include a suspension part at one end opposed to at least two openings.

The flexible container described in the first aspect of the present invention may further include three openings, each opening establishing fluid communication with a chamber different from the first second chambers and at least one additional chamber.

The flexible container described in the first aspect of the present invention may further include a suspension portion, which defines the high edges of the first and second chambers and at least one additional chamber.

The flexible container described in the first aspect of the present invention may further include a component of a parenteral formulation for fluid restricted patients in each of the first and second chambers and at least one additional chamber, one component comprising cysteine.

The flexible container described in the first aspect of the present invention may further include a suspension portion with an opening for suspending the container on a support or hook.

In a second aspect of the present invention, a flexible container for storing medical products is provided. The flexible container comprises: a first end and a second end; a first chamber positioned at one side end of the container; a third chamber positioned at an opposite side end of the container, and a second chamber positioned between the first and third chambers; a first frangible barrier between the first chamber and the second chamber, and a second frangible barrier between the second and third chambers; a first aperture positioned at the second end of the container and establishing fluid communication with one of the first and second chambers, and a second aperture positioned at the second end of the container and establishing fluid communication with the third chamber; a suspension portion extending from the first end of the container, the suspension portion defining an edge each of the first, second and third chambers, the suspension portion extending towards the second end at a substantially greater distance with respect to the at least second chamber than either of the at least second chamber.

The flexible multilayer container described in the second aspect of the present invention, wherein the suspension portion may extend toward the second end at a substantially greater distance from the second chamber and one of the first and third chambers, than the other of the first and third chambers.

The multilayer flexible container described in the second aspect of the present invention, wherein the multilayer flexible container bearing from the first end may activate one of the first and second peelable seals before activating the other of the first and second seals. detachable.

The flexible multilayer container described in the second aspect of the present invention, wherein the first and second foldable barriers may be peelable seals.

The multilayer flexible container described in the second aspect of the present invention may further include a third aperture which establishes fluid communication with the other of the first and second chambers. The multilayer flexible container described in the second aspect of the present invention, wherein the The suspension portion may further include an opening for suspending the container on a support or hook.

In a third aspect of the present invention there is provided a flexible multilayer pouch for storing and mixing medical products. The multilayer pouch comprises: upper part, lower part, first and second side side; a first chamber, a second chamber and a third chamber; a first frangible barrier, which separates the first and second chambers and a second frangible barrier, which separates the second and third chambers; and at least two apertures located on the underside, each aperture providing access to a different chamber from the first, second and third chambers; wherein the first, second and third chambers are arranged such that rolling of the pouch from the upper side activates one of the first and second frangible barriers before activating the other of the first and second foldable barriers.

The flexible multilayer pouch described in the third aspect of the present invention, wherein the first and second frangible barriers may be peelable seals.

In a fourth aspect of the present invention there is provided a flexible multilayer pouch for storing and mixing medical products. The multilayer pouch comprises: upper part, lower part, left side and right side; a first chamber, a second chamber and a third chamber; a plurality of frangible barriers which separate the first, second and third chambers from one another; and at least two openings located on the underside, each opening giving access to a different chamber from the first, second and third chambers; wherein the first, second and third chambers are arranged such that rolling of the pouch from the intersection between the upper side and one of the left and right sides enables activation of sequential frangible barriers.

The multilayer flexible pouch described in the fourth aspect of the present invention, wherein the first and second frangible barriers may be peelable seals.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 is a plan view of a 300 ml container embodiment of the present invention.

Figure 2 is a cross-sectional view of the container of figure 1.

Figure 3 shows a typical rolling method for opening all seals of a multi-chamber container.

Figure 4 is a plan view of the container of figure 1 after activation of the seals.

Figure 5 is a plan view of a 500 ml container embodiment of the present invention.

Figure 6 is a plan view of a 1000 ml container embodiment of the present invention.

Figure 7 is a plan view of another embodiment of the present invention.

Figure 8 is a plan view of another embodiment of the present invention.

Figure 9 is a plan view of another embodiment of the present invention.

Figure 10 is a cross-sectional view of one embodiment of a flexible film material used to construct the container of the present invention.

Figure 11 is a cross-sectional view of one embodiment of a flexible film material used to construct the container of the present invention.

Figure 12 is a graph depicting Absorption Units over time of the first and second oxygen indicator modalities stored at three different temperature conditions.

Figure 13 is a graph of the optical densities of an oxygen indicator modality of the present invention. Figure 14 is a graph of Absorption Units over time of an oxygen indicator modality of the present invention. inscribed on an exponential curve.

Figure 15 is a graph depicting Absorption Units over time of one embodiment of an oxygen indicator of the present invention stored at three different temperature conditions.

Figure 16 shows the reduced shape colors of an oxygen indicator samples of the present invention stored at 25 ° C / 40% RH and categorized by Pantone® references.

Figure 17 shows the reduced shape colors of samples of an oxygen indicator of the present invention, stored at 30 ° C / 35% RH and categorized by Pantone® references.

Figure 18 shows the reduced shape colors of an oxygen indicator samples of the present invention stored at 40 ° C / 25% RH and categorized by Pantone® references.

Figure 19 shows the reduced shape colors of samples of an oxygen indicator of the present invention after 2000 Iux illumination with a 30 day daylight tube at 25 ° C and categorized by Pantone® references.

Figure 20 shows the colors of the oxidized shape of oxygen indicator samples of the present invention stored at 25 ° C / 40% RH and categorized by Pantone® references.

Figure 21 shows the oxidized shape colors of oxygen indicator samples of the present invention, stored at 30 ° C / 35% RH and categorized by Pantone® references.

Figure 22 shows the oxidized shape colors of samples of an oxygen indicator of the present invention stored at 40 ° C / 25% RH and categorized by Pantone® references.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention, a flexible multi-chamber container is provided for storing separately medical solutions prior to use and facilitating selective activation of the frangible barriers separating the chambers. The container is preferably constructed to allow storage of aqueous formulations or delipids without the leaching problems described above and to facilitate selective opening of the frangible barriers separating the chambers.

Figure 1 illustrates one embodiment of a multiple camera container of the present invention. Preferably, the container 10, which is configured as a pouch, includes three adjacent chambers, or chambers 12, 14 and 16. Chamber 12 is located at one side or slanted end 18 and chamber 16 is located at an opposite side or slanted end 20. The three chambers 12, 14 and 16 are preferably configured to hold aqueous solutions and / or lipid emulsions. As shown in Figure 1, the container 10 has a total fluid capacity of 300 ml, with chamber 12 having a fluid capacity of 80 ml, chamber 14 having a capacity of 160 and chamber 16 having a capacity of 60 ml. ml.

Preferably, frangible barriers or rupturable seals 22 and 24 are used to separate the chambers. Figure 2 shows a cross-sectional view of container 10 and illustrates how breakable seals 22, 24 separate formulations contained in chambers 12, 14, 16. Breakable seals may be in the form of peelable seal or frangible seals. . Breakable seals allow formulations to be stored separately and mixed just prior to administration, thereby allowing storage in a single container of formulations that could not be stored as a mixture for an extended period of time.

The breaking of the seals enables communication between the chambers and the mixing of the contents of the respective chambers. Although containers with frangible seals are known, it is very difficult, if not impossible, to selectively open only one or less of all seals using the typical multi-chamber pouch rolling method. Selective activation of the seals is desirable because there are times when one of the three formulation container formulations should not be administered. The selective opening of the seals is described in more detail below.

The container 10 preferably also includes the openings 26,28 and 30 at the lower end 32 of the container to establish communication in each case with the chambers 12, 14 and 16. One or more of the openings may be constructed for use as an additive opening to allow the addition of materials such as micronutrients and / or may be constructed as an administration opening. Preferably, aperture 28 is an administration aperture and includes a membrane that can be pierced by a hypodermic cannula or needle of an administration set to provide the contents to a patient, and aperture 26 is for additions. In an alternative embodiment, there are two delivery ports 28, 30, whereby the mixture of formulations housed in chambers 12, 14, such as a mixture of amino acid solution and glucose, may be administered separately, or, if desired, at a different rate than formulation housed in chamber 16, such as a lipid emulsion. Of course, any number of openings can be used. In addition, the openings may be positioned in any number of ways; but it is preferred that the access openings are located at the same end of the container to allow more efficient production and filling of the chambers. In another embodiment, one of the seals 22, 24 is made of removable or detachable, while the second seal is made permanently. This allows two of the chambers to be mixed while one of the chambers remains permanently separated. Mixing and separate solution can then be administered separately, without the need for selective activation of breakable seals. The administration apertures are then provided in two of the chambers, so that an administration aperture is provided so that the chamber separated by the permanent seal can be administered while a second administration aperture is provided to allow the mixture to be dispensed. administered.

At the upper end 34 of container 10, preferably the opposite end 32 from which the delivery openings (s) are located, a suspension part 36 is provided, which in the embodiment shown in Figure 1 is a flap with a hole38. centrally located to hold the container. The flap 36 defines an edge 40 of the upper end of all chambers 12, 14 and 16. The central portion 42 of the suspension flap 36 preferably extends a substantial distance toward the lower end 32 of the particularly preferably about one quarter of the longitudinal length L of the container and especially preferred about one third of the length L of container 10. Preferably, flap 36 extends over a distance to the lower end 32 in the central chamber 14 and one of the other chambers 12, 16. This extra length of flap 36 with respect to the central chamber 14 results in the fact that chamber 14 has a shorter longitudinal length than that the longitudinal length of the side or side end chambers 12, 16. The longitudinal length of the central chamber should be from about two thirds to about three quarters of the longitudinal length of at least one of the side end chambers. This configuration allows selective opening of the seals as described below. The longitudinal length of the chambers is measured from their respective upper edges to their respective lower edges. For curved or uneven edges, the longitudinal length is the average of the longitudinal lengths measured continuously along the edge.

Before describing how the configuration of chambers 12, 14, 16 and / or suspension flap 36 facilitates selective opening of chamber seals 22, 24, it would be instructive to describe the typical method of opening seals 22,24.

Figure 3 illustrates the typical rolling method of opening the seals 22, 24, for mixing the contents of the chambers 12, 14 and 16. The release tab 36 or upper end 34 is rolled on itself in a clamping motion. In multiple chamber pockets, where all chambers extend substantially the same distance from their respective lower edges to their respective upper edges, rolling the pouch over pressurizes all chambers, risking an undesired activation of the seal. wrong. Also, multiple chamber pockets, with a central chamber extending farther from its lower edge to its upper edge than the other side end chambers, the pocket trim would pressurize the central chamber and randomly activate one or more seals adjacent to the central chamber. . However, the multiple chamber containers of the present invention include chamber arrangements to facilitate selective activation of the seals.

In container 10, chamber 14 does not extend as far towards the upper end 34 as chambers 12 and 16, i.e. chamber 14 is about three quarters of the longitudinal length of other chambers 12, 16; therefore, rolling the pouch from the upper end 34 pressurizes only chambers 12 and 16. In order to selectively activate only one of the seals 22, 24, only the end chamber adjacent to the enclosure to be activated is tightened with a continuation of movement. rolling bearing. Due to the length of the suspension flap 36, the central chamber 14 is not pressurized, preventing activation or partial activation of the second detachable seal. Additional rolling and tightening of the opposite side end chamber activates the other seal. Thus, sequential activation of the container seal of the present invention is possible. Consequently, the formulation which does not need to be administered at this time should therefore be housed in one of the chambers located at the lateral ends of the container.

Specifically, if the user wishes to activate only seal24, the user may begin to roll pouch 10 at the upper end 34. Without pressurizing chamber 14, the user may tighten the pouch at chamber 12. When seal 24 is activated, the User can stop fretting and tightening. If the user wishes to activate the two seals 22, 24, instead, the pouch 10 may be rolled from end 34 while the two chambers 12,16 are tightened.

Referring briefly to Figure 4, after seals 18 and 20 have been opened, the contents of container 10 can be mixed by manipulating the container and then administered to the patient by first suspending the pouch from a hook using hole 38.

Another rolling technique is also used to activate multi-chamber bag pockets. Referring to Figure 1, this technique also uses a rolling motion, except that instead of from the upper end 34, the container 10 may be rolled from one of the upper end corners 44, 46. Again, in pockets of multiple cameras, where all chambers extend substantially at a distance from the bottom, i.e. have substantially equal longitudinal lengths, or pockets with a central chamber extending a greater distance from the lower end to the upper than In the other end chambers, that is, a central chamber with a longer longitudinal length than any of the other chambers, rolling from one corner places too much pressure on a central chamber, risking unintended activation of the wrong seal. Using such a container tipping method of the present invention would not result in the activation of an unwanted seal or at least not so often.

In the arrangement of container chambers 10, selectively activating seal 24 using the corner rolling technique is as follows. Container 10 is rolled from corner 44. Rolling continues until chamber 12 is sufficiently pressurized to cause seal 24 to activate. Chamber 12 may also be tightened to prevent the container from being rolled too far. Since chamber 14 does not extend toward the upper end 34 as far as chamber 12, biasing is not sufficient to pressurize chamber 14 to a degree necessary to activate seal 22 at the time when seal 24 is activated.

Therefore, if chamber 14 extended the length of the container to the same degree as chamber 12, much more attention and care would have to be taken to prevent inadvertent pressurization of chamber 14 if this could be accomplished.

Two other embodiments of the container of the present invention are shown in FIGS. 5 and 6. Containers 110 and 210 shown in each case in FIGS. 5 and 6 also include, in each case, three chambers112, 114 and 116 and 212, 214 and 216. Containers 110 and 210 are constructed using the same materials and methods as those used in container 10. The only significant difference is the size and capacity of the containers 10, -110 and 210. As illustrated in 5, in a preferred embodiment, container 110 has a fluid capacity of 500 ml, with chamber 112 having a fluid capacity of 221 ml, chamber 114 having a capacity of 155 ml, and chamber 116 having a capacity of 124 ml. .

As shown in Figure 6, in a preferred embodiment, container 210 has a fluid capacity of 1000 ml, with chamber 212 having a fluid capacity of 392 ml, chamber 214 having a capacity of 383 ml and chamber 216 has a fluid capacity of 225 ml.

The containers 110 and 210 also preferably include peelable seals, in each case 122 and 124 and 222, 224, which separate the chambers and allow the chambers to open to enable communication between chambers and mixing of the contents of the chambers. The two containers 110 and 210 also include suspension flaps 136 and 236, which in each case include suspension holes 138 and 238.

Like container 10, containers 110 and 210 have non-suspending parts or flaps and chambers that are configured to facilitate selective activation of seals. For example, the containers 110, 220, have suspension flaps 136, 236 extending toward the lower ends 132, 232 (about one quarter to about one third of the longitudinal length of the container 110, 210 ), in each case more with respect to the central chambers 114, 214. Consequently, most of the area of the chambers 114, 214 with a longitudinal length which is about two thirds to about three quarters smaller than the one. longitudinal length most of the area of their respective side end chambers 110, 116 and 212, 216. Roll the containers 110, 210 from each upper end 134, 234 or one of the corners 144, 146 244,246, permits the rolling of the containers 110, 210 and the tightening of the chamber adjacent to the seal to be selectively activated without undue pressure being placed on the central chambers 114, 214, which would cause unintended activation of the other seal.

Containers 110 and 210 also include in each case access openings 126, 128 and 130 and 226, 228 and 230. These openings are constructed using the same materials and similarly as access openings 26, 28. and 30. To enable the same equipment to fill containers 10, 110 and 210, it is preferable to position them at the same distance from each other. Figures 7, 8 and 9 illustrate other embodiments of a multiple chamber container of the present invention. Containers 310,410, 510 all include three adjacent chambers, in each case 312, 314,316 and 412, 414, 416 and 512, 514, 516. Chambers 312, 412, 512 are located, in each case, at side ends. or side, 318, 418, 518, and chambers 316, 416 and 516 are located at opposite or opposite side ends 320, 420, 520. Suspension portion 336 is located at upper end 334 and includes hole 338 for suspending the container . Suspension part 336 defines the upper edge 340 of chambers 312, 314,316. Chamber 312 is separated from chamber 314 from chamber 314 by peelable seal 324, and peelable seal 326 separates chamber 314 from316. Container 410 also includes detachable seals 424, 426, which in each case separated chamber 412 from chamber 414 and chamber 414 from chamber 416. Detachable seal 526 separates chamber 514 from 516. Detachable seals allow detachable storage of discrete formulations in the chambers for subsequent mixing prior to administration.

Chamber 314 has a longitudinal length which is from about two thirds to about three quarters of the longitudinal lengths of two side end chambers 312, 316. Although the longitudinal lengths of chambers 312, 316 are the same, different lengths may be used. Selective activation of one of the detachable seals324, 326 on the container bearing 310 may begin at the upper ends 334 and tighten chamber 312 or chamber 316, depending on which detachable seals 324, 326 must be activated.

As shown in Figure 8, the side end chamber 416 of container 410 has a longitudinal length that is about two thirds to about three quarters smaller than the length of chamber 412, positioned at the opposite side end 418 and is equal to Longitudinal section of side end chamber 416. Chamber 412 with a longitudinal length greater than that of chamber 414 allows detachable seal 424 to be activated without inadvertently activating detachable seal 426 by rolling container 410 from upper end 434 .

Container 510 shown in Fig. 9 includes chambers 512,514, 516, all of which have longitudinal lengths differing from one another. The side end chamber 512 has a longitudinal length which is from about twenty five percent to about thirty percent longer than the longitudinal length of the chamber 516. The bearing of the container 510 from the upper end 534 allows selective activation of detachable sealing 524, 526, primarily by pressurizing chamber 512, until sealing 524 is activated. The additional bearing begins with chamber pressure 514 until seal 526 is activated. Any additional camera included between chamber 512 and 514 and having a longitudinal length less than the longitudinal length of chamber 512, but greater than the longitudinal length of chamber 514, or between chamber 514 and 516 and a shorter longitudinal length than the longitudinal length of chamber 514, but longer than the longitudinal length of chamber 516 may enable sequential activation of seals, starting with chamber 512 adjacent to the seal and ending with chamber adjacent to seal 516, by rolling the container from from the upper end 534.

One or more of the chambers is considered to be capable of storing a non-liquid, such as a powder or crystalline solid, with at least one chamber containing a liquid to dissolve the solid when communication is established between the chambers.

Figure 10 is a cross-sectional view of a film or foil embodiment 48 used to construct container 10. Preferably, sheet 48 is made of four layers 50, 52, 54 and 56. The outer layer 50 is preferably formed of of a polyester material such as a CHP beaker. This CHP copolyester is sold by Eastman Kodak under the name Ecdel 9965. A typical outer layer thickness50 is about 9.9 μηη (0.39 mil) to about 18.08 μηι (0.71 mil) where the effective thickness of the outer layer shown in Figure 3 is 13.97μηη (0.55 mil).

A bonding layer 52 is provided for securing the first layer 50 to a third layer 54. Preferably, the bonding layer is a highly reactive polymer adhesive such as maleic acid chemically modified EVA copolymer. This material is obtainable from DuPont1 under the name of Byner E-361. Bonding layer 52 may have a variable thickness, for example, from 5.08 μιτι (0.20 mil) to 15.24 μτη (0.60 mil), for example 10.10 μιτι (0.40 mil).

The third layer 54 is preferably a radiofrequency (RF) reactive polymer, such as an EVA copolymer. This material is available from DuPont under the name Elvax 3182-2. Preferably, the third layer has a thickness of about 141.22 μιτι (5.56 mil) to 173.73 μιτι (6.84 mil), for example 157.48 μιτι (6.20 mil).

Such film also includes a sealing layer 56: a) a bulk polyolefin that is thermally stable at thermal sterilization temperatures but melts below the outer layer melt temperature; such polymers are preferably polypropylene ethylene copolymers such as Total types Z9450 or 8650; and 2) a thermoplastic elastomer which produces a more flexible, free radical resistant seal layer and gives the seal layer two melting points, the elastomer having the smallest value; such polymers are preferably styrene-ethylene-butene-styrene block copolymers such as Kraton Kr-1652 from Kraton. The sealing layer preferably has a thickness of about 32.51 μιη (1.28 mil) to about 48.77 μπι (1.92 mil), for example 40.64 μιτι (1.60 mil) . The sealing layer 56 is adjacent to the inner side of the container 10 (Figure 1), so that when the seal is broken, communication is established between the chambers.

The container 10 is constructed by overlapping two sheets on top of one another or bending one sheet on itself or flattening an extruded tube if a tubular extrusion is used. Figure 10 shows two sheets 48 and 48a, the layer 56 being in contact with the corresponding layer 56a of sheet 48a. The sheets 48 and 48a are permanently joined or welded together at the perimeter, taking into account the placement of access openings. The sheets are also joined together in another area to form the outer contours of the chamber which will be formed later. Hot seals are formed to create multiple chambers.

The peelable seals are preferably formed using a heated sealing bar to heat and soften the layer 56, but do not liquefy the layer. A resulting cohesive union is formed by contact between sheet 48 and sheet 48a, but fusion between the sheets, which may result in permanent union, does not occur. Detachable seals may be formed to require a force of about 16 to about 21 Newtons to open or activate detachable seals, preferably about 19N.

In order to obtain this activation force, the temperature of the sealing bar varies depending on the material used to construct the container. For film 48, the sealing bar may be heated from about 116 to about 122 ° C, preferably about 118 ° C. It should be noted that this temperature may vary substantially between different batches of the same film material and that the cohesive joint of the peel seal is slightly strengthened or enhanced by thermal sterilization.

A more detailed explanation of the formation of the removable seal is described in U.S. Pat. 6,319,243, which is incorporated herein by reference.

Referring to Figure 1, apertures 26, 28 and 30 may be constructed by any number of methods and a plurality of materials. The openings can be made of tubes coextruded with clear PVC material inside to allow solvent bonding in normal PVC closure systems. Alternatively, non-PVC pipes may be used. but if one of the beds should contain a lipid, for example chamber 16, then aperture 30 is preferably constructed of a non-PVC material. If no administration site is added to the lipid-containing chamber opening, the opening is particularly preferably formed of a one-layer extruded tube of the following preferred formulation:

60% Total Polypropylene 8473

40% KratonG1652 styrene-butylene-styrene copolymer.

This opening is then sealed after filling.

If an administration site is added to the lipid-containing chamber aperture, the aperture is particularly preferably formed of a three-layer coextruded tube with the following preferred formulations:

Outer layer (± 330 μιτι):

100% polypropylene Solvay Eltex PKS490

or

60% Total Polypropylene 8473

40% Styrene-ethylene-butylene-styrene copolymer KratonG1652

Center layer (± 170 μιη):

35% Polypropylene Fortilene 426525% Polyethylene Tafmer A4085

10% Styrene-ethylene-butylene-styrene copolymer KratonFG1924

or

G1660

10% Polymydia MacromeItTPXI 6-15920% EVA Escorene UL00328

50% Styrene-ethylene-butylene-styrene copolymer Kraton

38% Polyester Dupont Hytrel 405610% EVA AT Plastic Ateva 2803G2% Polypropylene Total 6232Inner Layer (± 330 μπι):

50% EVA Escorene UL00119

50% EVA Escorene UL00328

or 50% EVA Ateva 2803G

50% EVA Ateva 1807G

In a preferred embodiment, some or all of the openings 22, 24 and 26 may be constructed of a non-PVC material, such as the above formulation.

Example 1

A comparison was made of a 300 ml multi-chamber container of the present invention, best exemplified by container 10, which was compared to a currently available multi-chamber container, which "was in all respects the same as container 10 except that the flap The suspension flap extended only half the distance in the central chamber as the suspension flap 36 extends into the chamber 14, making the central chamber of this bag slightly larger in capacity. water while the other side-end chamber was filled with a color solution Additional water was added to the central chamber to compensate for increased volumetric capacity In other words, although the central chamber of the container 10 had a volume smaller than the central chamber of the other container, they were similarly inflated with water.

Twenty operators were selected (10 men & 10 women). Each operator will receive 5 units of each model and the following instructions.

Instructions: For the ten containers, the bearing procedure from the suspension end of the container is required to open only the detachable seal separating the two compartments filled with colorless water. The detachable seal separating the compartment filled with blue water should not be opened.

Operators were asked "Which model allows easier and more efficient activation of just one detachable seal of the bag?" All twenty selected containers 10 of the present invention.

In a different embodiment of the present invention, six parenteral nutrition (PN) formulations are provided to three patient populations. Patient populations range from preterm infants (PT) to two-year-olds (TT), and children older than two years (OT). The PN formulation may have three components, which are stored separately and mixed prior to administration. The three components may be a carbohydrate component, an amino acid (AA) component and a lipid component. One or more electrolytes may also preferably be included in the PN formulation. Electrolytes may be included in one or more of the components or may be added by the healthcare professional either before or after the combination of the components. Preferably one or more electrolytes may be included in the carbohydrate components, but particularly preferably one or more of the electrolytes are included in the amino acid component.

The three components of the preterm PN formulation are preferably stored in a three chamber container separated by rupturable seals, such as frangible or peelable seals, with a total capacity of about 300 ml and the ability to open seal. the seals, particularly preferably in the container 10 (figure 1) described above. The three components of the term congratulatory PN formulation for two-year-olds are preferably stored in a similar three-chamber container, except that the recipient has a total capacity of about 500 ml, particularly preferably. in container 110 (Figure 5) described above. The three components of the PN formulation for children over the age of two are preferably stored in a similar three-chamber container, except that the container has a total capacity of about 1000 ml, particularly preferably. in container 210 (Figure 6) described above.

The carbohydrate component may include an aqueous solution, which contains from about 10% to about 70% of one or more carbohydrates, such as glucose, fructose and or saccharin. The amino acid component may include an aqueous solution containing from about 3% to about 10% of one or more amino acids. The lipid component may include an emulsion which contains from about 10% to about 30% lipids, such as fatty acids and / or triglycerides from animal, vegetable or synthetic sources, such as, but not limited to, olive oil. , Medium Chain Triglyceride Oil, Soybean Oil and Fish Oil. All percentages are expressed in weight to volume (w / v) unless otherwise specified.

Several members of the scientific community have determined recommended average nutritional guidelines (MNRG) for amino acid, carbohydrate and lipid components, and the minimum to maximum probable nutritional guidelines (MMNG) for electrolytes, see below, per kilogram per day for three patient populations as shown in the table below:

<table> table see original document page 26 </column> </row> <table>

* The ratio of calcium to phosphorus should be between 1: 1 to 1: 1,1.

Referring to Figure 1, in one embodiment of the present invention a preterm baby PN formulation is made available in container 10. The PN formulation may include an amino acid component which may comprise a solution including water for injection, acidic acid for pH adjustment to about 5.5 and the following amino acids:

<table> table see original document page 26 </column> </row> <table> <table> table see original document page 27 </column> </row> <table>

Although the above amino acids, in their respective amounts, are preferred, other amino acids in different amounts and combinations may be used. Nevertheless, cysteine must be present in amino acid solutions; specifically, those given to preterm infants because cysteine is a conditionally essential amino acid and because preterm infants have limited ability to synthesize cysteine.

The PN formulation may also include a delipid component, which may comprise of a 12.5% lipid emulsion in water for injection.

<table> table see original document page 27 </column> </row> <table>

Olive oil is a preferred lipid because of its desirable immunoneutrality. The above combination is preferred because the combination causes less peroxidation and no additional oxidative stress. Although these are the preferred lipids and the preferred lipid concentration, other sources of lipids may be used, such as animal, vegetable or synthetic lipids.

The PN may also include a carbohydrate component, which may comprise a 50% aqueous glucose and electrolyte solution, as shown in the table below: <table> table see original document page 28 </column> </row> <table>

Other sources and amounts for electrolytes and carbohydrates may be used. It is preferred that phosphorus originates from organic sources and the table indicates especially preferred sources of nutrients. It is also preferred that the pH be adjusted to about 4.0 and in the preferred embodiment, the adjustment is obtained using hydrochloric acid, along with other pH regulators such as malic acid or acetic acid, to also achieve the desired chloride level.

Referring to Figure 1, each chamber of container 10 is filled with one of the components of the PN formulation. Particularly, the containers of a preterm baby PN formulation may include about 80 ml of the carbohydrate component in chamber 12, about 160 ml of the amino acid component in chamber 14 and about 60 ml of lipid component in chamber 16. In some cases, it may not be recommended to administer the lipid component as if it is the first day if the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level or other reasons. In this case, the container 10 allows the selective opening of the seal 24.

In order to provide MNRG (or nutrition at least to the minimum of MMNG), about 120 ml of the PN formulation should be infused per patient's kilogram per day. The 300 ml container would then contain sufficient PN for a 2.5 kg neonate over a 24 hour period. The table below illustrates the approximate values of PN formulation in a three-chamber container. <table> table see original document page 29 </column> </row> <table>

In one embodiment, administration of about 120 ml / kg / day of the above PN formulation to preterm patients provides the following nutrients and electrolytes:

<table> table see original document page 29 </column> </row> <table>

It is desirable to provide calcium and phosphate levels above the lower level than the recommended average requirements. However, increasing sodium glycophosphate causes the sodium level to exceed the upper dolimite level of recommended average requirements. Although calcium can easily be increased by adding more calcium chloride, this would change the recommended calcium to phosphorus ratio of 1: 1 or 1: 1.1. In one fashion, an inorganic form of phosphorus is added to the α-minoacid component to meet the recommended average requirement. In conjunction with this addition, more calcium is preferably added to maintain proper arelation.

It may be desirable to provide less fluid than the recommended average, so that other fluid therapy may be provided by the healthcare provider. This fluid therapy is often required in patients who need PN. To enable the administration of other fluids, 120 ml / kg / day was chosen to be supplied in nutritional volume, while the total fluid intake required in preterm neonates is 150-170 ml / kg / day.

Referring to Figure 5, in another embodiment of the present invention, a PN formulation for term infants to two-year-olds is provided in a three-chamber 500 ml container, preferably container 110. PN may include a carbohydrate component which may be housed in an end chamber 112 having a volumetric capacity of about 155 ml and a longitudinal length substantially greater than the longitudinal length of the central chamber 114. This allows selective opening of seal124 adjacent to carbohydrate-containing chamber 112 without opening seal122 adjacent to chamber 116. An amino acid component may also be included in the PN formulation and may be housed in a central chamber114 with a volumetric capacity of about of 221 ml. Also a lipid formulation may be included in the PN formulation and may be housed in an end chamber 116, with a volumetric capacity of about 124 ml. The lipid and amino acid components may be formulated as described above. The carbohydrate component may comprise a 50% glucose and electrolyte solution, as shown in the table below:

<table> table see original document page 30 </column> </row> <table>

Other sources, quantities and combinations for electrolyte and carbohydrate may be used. It is preferred that phosphorus in the carbohydrate component originates from organic sources and the table indicates the particularly preferred sources of nutrients. Each chamber is filled with one of the components. Particularly, about 155 ml of the carbohydrate component may fill an end chamber 112, as described above, about 221 ml of the amino acid component may fill a central chamber114, as described above, and about 124 ml of the lipid component can fill an end chamber 116 as described above. The detachable seal 124 described above allows blending of the carbohydrate and amino acid components or all seals 122, 124 can be opened to create the ternary PN formulation. Thus, in some cases where it is not recommended to administer the lipid component, such as if it is the first day of life, if the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level or other reasons, the container permits selective opening of only the seal adjacent to an end chamber substantially longitudinally longer than the longitudinal length of a central chamber, resembling the seal adjacent the lipid chamber as described above.

In order to provide the MNRG and at least the minimum MMNG1 about 96.7 ml / kg / day of the PN formulation should be infused per patient's kilogram per day. The 500 ml container then provides sufficient PN for a child of about 5 kg for a period of 24 hours. The table below illustrates the approximate values of the PN formulation in a three-chamber container:

<table> table see original document page 31 </column> </row> <table>

Administration of 96.7 ml / kg / day of the formulation for at-term babies to two-year-olds provides approximately the following nutrients and electrolytes:

<table> table see original document page 31 </column> </row> <table> <table> table see original document page 32 </column> </row> <table>

With the addition of all Iipidios1 phosphorus intake is higher and the P / Ca ratio increases, but this patient population can reconcile this small excess of phosphorus. The reduced amount of fluid allows the healthcare professional to administer another fluid therapy if necessary, which may be advantageous in certain circumstances.

Referring to Figure 6, in another embodiment of the present invention, a PN formulation for children above two years of age is provided in a 1000 ml three-chamber container, preferably container 210. The PN formulation may include a carbohydrate component, which may be housed in an end chamber 212, with a volumetric capacity of about 383 ml and a longitudinal length substantially greater than the longitudinal length of the central chamber 214. This allows selective opening of the seal 224 adjacent chamber 212 containing carbohydrate without opening seal 222 adjacent chamber 216. An amino acid component may also be included in the PN formulation and may be housed in a central chamber 214 with a volumetric capacity of about 392 ml. In addition, a deliphilium component may be included in the PN formulation and may be housed in an end chamber 216 with a volumetric capacity of about 225 ml. The lipid and amino acid components may be formulated as described above. The carbohydrate component may comprise a 50% glucose and electrolyte solution as shown in the table below: <table> table see original document page 33 </column> </row> <table>

Other sources, quantities and combinations for electrolyte and carbohydrate may be used. It is preferred that phosphorus in the carbohydrate component originates from organic sources and the table indicates the particularly preferred sources of nutrients.

Each chamber is filled with one of the components. Particularly, about 383 ml of the carbohydrate component fills an end chamber 212 as described above, about 392 ml of the amino acid component fills the central chamber 214 as described above, and about 225 ml of the component. of lipid fills one end chamber 216 as described above. Each component may be administered to the patient separately or all seals 222, 224 may be opened to create the PN formulation. But in some cases, it may not be advisable to administer the lipid component, such as the first day of life, if the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level, or other reasons. The container allows selective opening of only the seal adjacent to an end chamber with the longitudinal length substantially greater than the longitudinal length of a central chamber, without opening the seal adjacent to the lipid chamber as described above.

In order to provide the MNRG and at least the minimum of MMNG, about 78.3 ml / kg / day of the PN formulation should be infused per patient's kilogram per day. The 1000 ml container then provides enough PN for a child of about 12.5 kg for a period of 24 hours. The table below illustrates the approximate values of the formulation of J3N in a three chamber container:

<table> table see original document page 34 </column> </row> <table>

Administration of about 78.3 ml / kg / day of the PN formulation to children over the age of two provides the following nutrients and electrolytes:

<table> table see original document page 34 </column> </row> <table>

The reduced fluid level enables the healthcare professional to administer other fluid therapy, which may be desirable under certain circumstances.

In another embodiment of the present invention, a PN formulation for children over two years of age is provided in a 1000 ml three-chamber container, preferably container 210. The PN formulation may include a carbohydrate component which may be housed. in an end chamber 212 having a volumetric capacity of about 332 ml and a substantially greater longitudinal length than the longitudinal length of the central chamber 214. This allows selective opening of seal 224 adjacent to the carbohydrate-containing chamber 212 , without opening seal 222, adjacent to chamber 216. An amino acid component may also be included in the PN formulation and may be housed in a central chamber 214 with a volumetric capacity of approximately 425 ml. A lipid component may also be included in the PN formulation and may be housed in an end chamber 216 with a volumetric capacity of about 243 ml. The lipid and amino acid components may be formulated as described above. In the preferred embodiment, the carbohydrate component may comprise a 62.5% glucose solution and electrolytes, as shown in the table below:

<table> table see original document page 35 </column> </row> <table>

Other sources, quantities and combinations for electrolyte and carbohydrate may be used. It is preferred that phosphorus in the carbohydrate component originates from organic sources and the table indicates the particularly preferred sources of nutrients.

Each chamber is filled with one of the components. Particularly, about 332 ml of the carbohydrate component fills an end chamber 212 as described above, about 425 ml of the amino acid component fills the central chamber 214 as described above and about 243 ml of the component. of lipid fills one end chamber 216 as described above. Each component may be administered to the patient separately or all seals 222, 224 may be opened to create the PN formulation. But in some cases, it may not be advisable to administer the lipid component, such as if the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level or other reasons. In such a case, the container permits selective opening of only seal 224, adjacent to an end chamber 212, of longitudinal length substantially greater than the longitudinal length of a central chamber 214, without opening seal 222, adjacent to lipid chamber 216 as described above.

In order to provide the MNRG and at least the minimum of MMNG, about 72.3 ml / kg / day of the PN formulation should be infused per patient's kilogram per day. The 1000 ml container then provides enough PN for a child of about 13.5 kg for a period of 24 hours. Thus, this container serves a larger child better for a 24 hour period than the 1000 ml chamber mode, as previously described. The table below illustrates the approximate values of PN formulation in a three-chamber container:

<table> table see original document page 36 </column> </row> <table>

Administration of 72.3 ml / kg / day of the above two-year-old formulation provides approximately the following nutrients and electrolytes:

<table> table see original document page 36 </column> </row> <table>

The reduced fluid level allows the healthcare professional to administer other fluid therapy, which may be desirable under certain circumstances.

In some cases, it has been determined that any increase in electrolyte concentration above the minimum level increases the carbohydrate component's buffering capacity (aqueous glucose and electrolyte solution). This increased buffering capacity results in the pH reduction of the mixed PN formulation to a level potentially incompatible with the target pediatric populations.

As a result, it may be preferable not to include electrolytes beyond the minimum concentration shown above, not to include electrolytes beyond the minimum concentration shown above in the formulation as produced, but to allow the addition of electrolytes by the healthcare provider prior to administration. , or include electrolytes, even at concentrations above the minimum basic level, in another component.

Therefore, in such cases, in particularly preferred embodiments of the present invention, three parenteral (PN) nutrient formulations are provided to the patient populations described above, that is, preterm infants (PT) term infants to children with two year old (TT) screens above two years old (OT). The particularly preferred PN formulation may have three components, which are separately stored and mixed prior to administration. The three components may be a carbohydrate component, an amino acid (AA) component and a lipid component. One or more electrolytes may also preferably be included in the PN formulation, particularly preferably several electrolytes are included in the amino acid component.

The three components of the preterm PN formulation are preferably stored in a three-chamber container, separated by breakable seals, such as frangible or peelable seals, with a total capacity of about 300 ml and the ability to open selec- particularly the seals, particularly in the container 10 (figure 1), described above. The three components of the term congratulatory PN formulation up to two-year-olds are preferably stored in a similar three-chamber container, except that the container has a total capacity of 500 ml, particularly preferably in the container 110 (figure 5), described above.

The carbohydrate component may include an aqueous solution, which contains from about 10% to about 70% of one or more carbohydrates, such as glucose, fructose and or saccharin. The amino acid component may include an aqueous solution containing from about 3% to about 10% of one or more amino acids. The lipid component may include an emulsion which contains from about 10% to about 30% lipids, such as fatty acids and / or triglycerides from animal, vegetable or synthetic sources, such as, but not limited to, olive oil. , Medium Chain Triglyceride Oil, Soybean Oil and Fish Oil. All percentages are expressed in weight to volume (w / v) unless otherwise specified.

A preferred lipid component for the PN formulation for all three populations (PT, TT and OT) comprises a 12.5% delipid emulsion in water for injection as previously described.

Olive oil is a preferred lipid because of its desirable immunoneutrality. The above combination is preferred because the combination causes less peroxidation and no additional oxidative stress. Although these are the preferred lipids and the preferred lipid concentration, other sources of lipids may be used, such as animal, vegetable or synthetic lipids.

A preferred carbohydrate component for the PN formulation for all three patient populations (PT, TT and OT) may comprise a 50% glucose solution in water for injection. One or more carbohydrates may be used in place of glucose. The pH should be adjusted to about 4.0 and in a preferred embodiment the adjustment may be carried out with hydrochloric acid.

A preferred amino acid component for the PN formulation for each of the three patient populations (PT, TT and OT) may comprise an amino acid and electrolyte solution. The approximate amounts of amino acid component constituents for each patient population are shown in table A below:

<table> table see original document page 38 </column> </row> <table> <table> table see original document page 39 </column> </row> <table>

Other sources, combinations and amounts for electrolytes and amino acids can be used. It is preferred that phosphorus comes from organic sources and the table above indicates particularly preferred sources of nutrients.

Referring to Figure 1, each container chamber 10 is filled with one of the PN formulation components. In particular, the containers of a preterm baby PN formulation may include about 80 ml of the carbohydrate component in chamber 12, about 160 ml of the amino acid component for the PT population in chamber 14, and about 60 ml of the lipid component in the chamber 16. In some cases, it may not be advisable to administer the lipid component, such as if the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level, or other reasons such as the first day. In this case, the container 10 permits the selective opening of the seals.

In order to provide MNRG for amino acids, carbohydrates, lipids and electrolytes, about 120 ml of the PN formulation should be infused per patient kilogram per day. The 300 ml container then provides sufficient PN for a 2.5 kg neonate (PT) for a 24 hour period. The table below illustrates the approximate values of the PN formulation in a three chamber container:

<table> table see original document page 40 </column> </row> <table>

In one embodiment, administration of about 120 ml / kg / day of PT formulation to preterm patients provides approximately the following nutrients and electrolytes:

<table> table see original document page 40 </column> </row> <table> It is desirable to provide calcium and potassium levels above the lower limit of the recommended average requirements. But increasing glycerophosphate causes the sodium level to exceed the upper scope of the recommended average requirements. Although calcium can be easily increased by the addition of more calcium chloride, it alters the recommended 1: 1 or 1: 1,1 ratio of calcium to phosphorus. In one embodiment, an inorganic form of phosphorus is added to the amino acid component to meet the recommended average requirement. In conjunction with this addition, more calcium is preferably added to maintain the proper ratio.

It may "be desirable to provide less fluid than the recommended average, so that other fluid therapy may be provided by the healthcare professional. Such fluid therapy is often required in patients who need PN. To allow On administration of other fluids, 120 ml / kg / day was chosen to provide nutritional volume, while the total fluid intake required in preterm infants was 150-170 ml / kg / day.

Referring to Figure 5, in another embodiment of the present invention, a PN formulation for term infants to two-year-olds is provided in a three-chamber 500 ml container, preferably container 110. PN may include a carbohydrate component, which may be housed in an end chamber 112, with a volumetric capacity of about 155 ml and a longitudinal length substantially greater than the longitudinal length of the central chamber 114. This allows for selective opening of seal124 adjacent to the carbohydrate-containing chamber 112 without opening seal122 adjacent to chamber 116. An amino acid component may also be included in the PN formulation and may be housed in a central chamber114 with a volumetric capacity of up to 100%. about 221 ml. Also a lipid formulation may be included in the PN formulation and may be housed in an end chamber 116, with a volumetric capacity of about 124 ml.

The lipid component can be formulated as described above and the amino acid component can be formulated for the TT population as shown in table A above.

A preferred carbohydrate component for the dePN formulation for all three patient populations (PT, TT and OT) can comprise a 50% glucose in water for injection. One or more carbohydrates may be used in place of glucose. In the preferred embodiment, the pH may be adjusted to about 4.0 with hydrochloric acid.

Each chamber is filled with one of the components. Particularly, about 155 ml of the carbohydrate component may fill an end chamber 112, as described above, about 221 ml of the amino acid component may fill a central chamber114, as described above, and about 124 ml of the lipid component can fill an end chamber 116 as described above. Optional peel seal 124, described above, allows mixing of the carbohydrate and amino acid components, or all seals 122, 124 can be opened to create the ternary PN formulation. . Thus, in some cases where it is not recommended to administer the lipid component, such as if it is the first day of life, if the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level or other reasons, the container allows Selectively opening the seal just adjacent to an end chamber, with the longitudinal length substantially greater than the longitudinal length of a central chamber, without opening the seal adjacent the lipid chamber, as described above.

In order to provide MNRG for amino acids, carbohydrate, lipids and electrolytes, about 96.7 ml / kg / day of PN formulation should be infused per patient kilogram per day. The 500 ml container then provides enough PN for a child of about 5 kg for a 24 hour period. The table below illustrates the approximate PN formulation values in a three-chamber container:

<table> table see original document page 42 </column> </row> <table> Administration of 96.7 ml / kg / day of the formulation for at-term babies to two-year-olds provides approximately the following nutrients and electrolytes:

<table> table see original document page 43 </column> </row> <table>

With the addition of all lipids, phosphorus intake is higher and the P / Ca ratio increases, but this patient population can reconcile this small excess of phosphorus. The reduced amount of fluid allows the healthcare professional to administer another fluid therapy if necessary, which may be advantageous in certain circumstances. Referring to Figure 6, in another embodiment of the present invention, a PN formulation for children over two years of age is provided in a 1000 ml three-chamber container, preferably container 210. The PN formulation may include a carbohydrate component, which may be housed in an end chamber 212, with a volumetric capacity of about 383 ml and a longitudinal length substantially greater than the longitudinal length of the central chamber 214. This allows selective opening of the seal 224, adjacent to the carbohydrate-containing chamber 212, without opening seal 222, adjacent to the chamber 216. An amino acid component may be included in the PN formulation and may be housed in a central chamber 214 with a volumetric capacity of about 392 ml. In addition, a lipid component may be included in the PN formulation and may be housed in an end chamber 216 with a volumetric capacity of about 225 ml.

The lipid component can be formulated as described above and the amino acid component can be formulated for the TT population as shown in table A above.

A preferred carbohydrate component for the PN formulation for all three patient populations (PT, TT or OT) can comprise 50% glucose in water for injection. One or more carbohydrates may be used in place of glucose. In the preferred embodiment, the pH may be adjusted to about 4.0 with hydrochloric acid.

Each chamber is filled with one of the components. Particularly, about 383 ml of the carbohydrate component fills an end chamber 212 as described above, about 392 ml of the amino acid component fills the central chamber 214 as described above, and about 225 ml of the component. of lipid fills one end chamber 216 as described above. Each component may be administered to the patient separately or all seals 222, 224 may be opened to create the PN formulation. But in some cases, it may not be advisable to administer the lipid component, such as the first day of life, if the patient is suffering from septic shock, coagulation abnormalities, high bilirubin level, or other reasons. The container permits selective opening of only the seal adjacent an end chamber, the longitudinal length substantially greater than the longitudinal length of a central chamber, without opening the seal adjacent the lipid chamber as described above.

In order to provide MNRG for amino acids, carbohydrates, lipids and electrolytes, approximately 78.3 ml / kg / day of PN formulation should be infused per patient kilogram per day. The 1000 ml container then provides sufficient PN for a child of about 12.5 kg for a period of 24 hours. The table below illustrates the approximate values of PN formulation in a three-chamber container:

<table> table see original document page 44 </column> </row> <table> Administering 78.3 ml / kg / day of the above PN formulation to children over two years of age provides approximately the following nutrients and electrolytes:

<table> table see original document page 45 </column> </row> <table>

The reduced fluid level allows the healthcare professional to administer other fluid therapy, which may be desirable under certain circumstances.

Referring to Figure 11, TPN formulation containers according to the present invention may be placed in selected pouches to preserve solution viability and protect the solution against degradation. In one embodiment of the present invention, an outer pouch is created to house a multiple chamber 10, 110, 210, 310, 410, 510 container containing a carbohydrate component, a lipid component and a amino acid component of a TPN formulation. The outer pouch is preferably constructed of a multilayer plastic film or sheet and prevents oxygen from entering the outer pouch. It is also preferred that the outer pouch be capable of resisting sterilization such as autoclaving.

One or more of the film layers used to build the outer shell may include oxygen scavenging polymers or the layer may create a physical barrier to prevent oxygen permeation.

Figure 11 shows a cross-section of a dofilm embodiment 310 used to construct the outer pouch. Preferred film 58 comprises 4 layers 60, 62, 64 and 66. Layer 60 is the outermost layer and is preferably a high temperature melt polymer with an oxygen barrier coating. As illustrated, layer 60 is a polyester material with an aluminum oxide coating 68. The thickened layer 60 may range from about 6 to about 18 μιη, preferably from about 10 to about 14 μιη. μιη, especially preferably about 12 μηι. The coating 68 may range in thickness from about 400Angstrom. The layer 312 is oriented such that the aluminum oxide coating faces toward the inside of the outer pouch.

Preferably, the next inwardly moving layer 62 is the same as layer 60 except that the coating 70 is facing the next. A different polymer with oxygen-impermeable qualities may be used in place of the scavenging polymer. oxygen.

The two layers 60 and 62 are joined or welded together in a multitude of ways. As shown in Figure 11, an adhesive 72 is placed between the layers 60 and 62. The adhesive may be applied in a thickness range of from about 1.5 to about 5.5 μιτι, preferably about 8 μιτι. of 3.5 μιτι. Although many different adhesives may be used, the preferred adhesive is a polyester polyurethane resin adhesive.

Layer 64 is preferably a nylon material, particularly preferably nylon-6. The thickness of layer 64 may be from about 10 to about 20 μηι, with the preferred thickness being about 15 μιη. Layer 64 is joined to layer 62 with adhesive 74, which in this mode is the same adhesive of equal thickness as adhesive 72.

Layer 66 is the innermost layer and is preferably a polypropylene material, particularly preferably a fused polypropylene. The thickness of the layer 66 may range from about 30 to about 70 μιη, particularly preferably about 50 μηι.

The layers 64 and 66 are also joined together with a adhesive 76, which in this embodiment is the same adhesive and has the same thickness as the adhesive 72.

In another embodiment, the outer pouch may be made of duastelas with different structures. The upper web may be the above described structure, while the lower web may be a thermoformed or opaque structure or may have a sealing layer allowing detachable opening.

A multiple chamber container 10 (FIG. 1), which stores it in a TPN formulation, is then placed in the outer pouch. Preferably, the free space of the outer pouch is filled with an inert gas such as nitrogen to remove atmospheric oxygen and then the outer pouch can be sealed. The outer pouch can be closed using an adhesive or by heat sealing. When the outer pouch is sealed, the entire package may be sterilized.

Thermal sterilization of amino acid solutions with a thiol function, such as cysteine or N-acetyl cysteine, is known to produce hydrogen sulfide gas as a decomposition product, and most likely also ppb levels of other sulfur compounds. organic, volatile, unidentified, noticeable by their odor. Hydrogen sulfide balances between the liquid phase and the gas phase or free space when present. A limit of 1 ppm hydrogen sulfide in the aqueous phase has been determined to be non-toxic to the patient intravenously. But even if this limit in the aqueous phase is applied, some hydrogen sulfide and related gas phase sulfur compounds may still be present at a very low level, but at a level sufficient to produce an unpleasant odor (the smell of hydrogen sulfide). can be felt at 0.1 ppm in the gas phase). This unpleasant odor can be disturbing to the patient and others in the area and create an impression that TPN formulation is deteriorated or contaminated.

In this regard, to remove any unpleasant odor linked to very low levels of hydrogen sulfide and / or gas-related sulfur compounds, before the outer pouch is sealed, an odor absorber (not shown) may be placed. in the outer bag. There are many types of absorbers that can be used and most contain active charcoal that attracts and binds molecules on the pore surface with Van der Waals forces mechanism. In addition, an oxygen absorber may also be placed in the outer pouch to absorb any oxygen that may still have been left in the outer pouch or which may diffuse through the outer pouch material during the storage period of the product. The oxygen absorber also has the ability to absorb H2S1 by establishing a covalent bond with iron to form iron sulfur. It is also considered that a combined oxygen and odor eliminator may be used.

It should be noted that the container housing the cysteine-containing NTP formulation must be permeable to hydrogen sulfide so that it can enter inside the outer pouch where it can be absorbed or disposed of.

In another embodiment of the present invention, sterilization at a temperature slightly higher than the industry standard of 121 degrees centigrade may be performed to reduce the level of hydrogen sulfide. For example, it has been found that sterilization at 125 degrees centigrade and for a shorter time period or sterilization cycle reduces hydrogen sulfide levels and reduces the degradation of some of the amino acids. With less degradation, formulated amino acid levels may be closer to desired levels after sterilization, which facilitates the ability to tightly control amino acid levels.

In another embodiment of the present invention, an oxygen indicator is provided. Oxygen indicators are used to demonstrate that the oxygen sensitive components of the TPN formulation, such as lipid emulsions, have not been exposed to undesirable oxygen levels during transport and / or storage. A preferred oxygen indicator produces a distinct and marked color change to indicate that oxygen is present even after thermal sterilization has been performed. Furthermore, when the color change has occurred, the oxidized color must then remain substantially visually unchanged for the observer in circumstances where the indicator is not observed for some time, such as during prolonged storage.

In one embodiment of an indicator, the indicator of the present invention is placed in the outer pouch and may be adhered to the medical container prior to sterilization. Thus, the indicator must be able to withstand steam sterilization. In other words, the indicator's reduced color, that is, the indicator color before oxygen exposure sufficient to oxidize the indicator, still changes color when oxidized (exposed to sufficient oxygen) and the oxidized color must remain substantially visually unchanged and different from the reduced color, in a preferred embodiment the indicator is produced in its oxidized form and is reduced in steam sterilization. In addition, both the color of the reduced form and the color of the oxidized form should not fade or change significantly during storage of up to three months at 40 ° C, particularly preferably up to six months at 40 ° C. In addition, both the reduced shape color and the oxidized shape color must not oxidize or change significantly during storage for up to two years at 25 ° C and 30 ° C.

Typically, oxygen indicators come in small bags that contain an indicator solution. The pouches are usually constructed of an upper screen and a lower or base screen which are enclosed around their edges to create a sealed pouch. An adhesive such as a two-sided tape may be placed. on the screen to secure the indicator pouch into the secondary or norecipient package housing the medical formulation. In a preferred embodiment, the indicator is attached to the surface of the oxygen absorber. The material forming the bag can be selected to meet the kinetic need or color change. Some of these materials may be:

upper screen: oriented polypropylene (OPP) 25μ / polypropylene deepened (CCP) 40 μ. A multiple color print can be applied between the OPP and CPP layers.

base mesh: polyethylene terephthalate (PET) 12 æg / oriented polypropylene (OPP) 20 μ / cast polypropylene 30μ. Any print, such as a white opaque print, can be placed between the PET layer and the OPP layer.

In one embodiment using the film described above, exposure of a micro-hole to an oxygen environment caused the indicator color to change in less than three days to indicate the presence of oxygen. The indicator solution includes indigo carmine, which changes from a yellowish color when reduced, indicating a lack of oxygen, to blue, when oxidized by the presence of oxygen.

The pouches are preferably constructed with a transparent portion to display the color of the indicator solution. The indicator solution is prepared under atmospheric conditions, which means that the indicator is in its oxidized blue color. During production, the pouch containing the oxidized form of the indicator solution is placed in an outer pouch with the container housing a TPN formulation and the outer pouch sealed and sterilized. During the sterilization cycle, the indicator solution is reduced and the solution turns yellow. The oxidation reduction reaction is shown below:

<formula> formula see original document page 50 </formula>

The reaction is reversible, that is, the solution turns blue again when exposed to oxygen. In a preferred embodiment, indicators should be formed using components that are non-toxic to the contents of the containers and to the users of the product, which may be exposed to indicator solution if there is a leak through a crack in the film. In a more preferred embodiment, the components consist of food additives, which are well known for their non-toxicity.

One embodiment of an oxygen indicator is based on a concentration of 3 g / l carmine indigo. The specific formulation is a mixture of 20 ml 1.5% indigo carmine, 80 ml 0.13 M sodium pyrophosphate and 18 g microcrystalline cellulose and pH adjusted to 8.75 withHCl. The oxidized color of this currently available oxygen indicator produces a blue color when oxidized, but this color degrades relatively quickly. After three months of storage at 40 ° C, the blue color fades to a skin color, which is not sufficiently different from the yellow color or reduced shape of the indicator. This faded color cannot provide unambiguous identification of oxygen exposure. Similar results were observed with samples maintained at 30 ° C for 8 months and at 25 ° C for 12 months.

In an attempt to overcome this deficiency, the carmine indigo concentration was increased to a concentration of 6 g / L and compared to the currently available indicator (reference). The table below gives details of each formulation.

<table> table see original document page 51 </column> </row> <table>

As cellulose is added to function as a reducing agent, the cellulose content has been increased in this second (alternative) mode of indicator to compensate for the increase in carmine indigo. In other words, more cellulose is required to ensure that the indicator will reduce during sterilization.

Samples of each indicator were analyzed for their optical densities in absorption units (AU) at 610 nm, which is the absorption range for the oxidized blue color after formulation, sterilization and storage at various temperatures, over time.

Results are shown in the table below.

<table> table see original document page 51 </column> </row> <table>

Day 0 means the solution before sterilization, while day 1 means the solution after sterilization.

A graphical representation of the above data is shown in Fig. 12.

Initial absorption after sterilization is about 1.4 AU, with the formulation of alternative 1 versus 0.8 AU for the first iteration. As shown in Figure 9, the downward trend is similar for two iterations. Longer oxidized color stability is expected, but the expected 24 month stability may be the limit for this formulation.

Other types of cellulose were also investigated using reference indicator formulation, specifically DS-O TLC delulose, colloidal microcrystalline cellulose, chromatography cellulose powder, chromatography acid washed paracellulose powder, carboxymethyl cellulose sodium salt, low and high viscosity, acetate cellulose and methyl cellulose. No major differences were observed between the formulations, including other insoluble cellulose compounds. Tests have shown that insoluble cellulose cannot be replaced by soluble grafted cellulose. In addition, EDTA has been investigated as an additive known as a stabilizing agent. Again, EDTA had no significant effect on oxidized indicator color degradation.

The further increase in carmine indigo concentration produced complications caused by the increase in cellulose content and it was found that increasing the level above 300 g / l of cellulose used in alternative indicator 1 made it difficult to produce the indicator bag and created a mixture undesirably similar to a paste. Any further increase would further exacerbate these aspects, but failing to increase the level of cellulose led to an inability to adequately reduce the higher levels of indigo carmine during sterilization.

It has been determined that adding an appropriate amount of reducing agent and, in a preferred example, a stronger reducing sugar, such as dextrose, enables the concentration of carmine indigo to be increased to a concentration beyond 6 g / l while the content of cellulose is maintained at the most preferred level of 180 g / l.

In one embodiment, the indicator solution includes, besides indigocarmine, a pH-adjusting buffer within the range of about 9.0 to about 9.75 prior to sterilization, and from about 7.0 to about 9.0. , after sterilization, cellulose and a reducing agent.

Carmine indigo is considered not to be a hazardous substance under European Community Directive 67/548 / EEC. The concentration of indigo carmine may be greater than 6 g / l and less than about 60 g / l, preferably from about 10 to about 40 g / l, particularly preferably from about 14 to about 40 g / l. 20 g / l, with a lower concentration producing a more attractive visual indicator. Carmine concentrations above 20 g / l still exceed the solubility limit and a lack of color homogeneity such as dark spots or portions is observed.

Buffers may include phosphate and acetate buffers. Specific buffers include sodium phosphate buffers and disodium acetate buffers, with a sodium pyrophosphate buffer being preferred. Sodium pyrophosphate is considered to be a non-hazardous substance under European Community Directive 67/548 / EEC. The concentration of desodium pyrosphosphate may be from about 0.11 M to about 0.18 M, preferably from 0.13 M to about 0.17 M. Other buffers may be suitable to reach the desired pH of 7-9 after sterilization. It has been observed that for the sterilization cycle that is used for these nutrition products, a pH of 9.0-10.0 prior to sterilization leads to the desired pH after sterilization.

Dyes and / or thickeners may include soluble cellulose compounds as they also have some reducing capacity and are an approved food additive. Preferred cellulose is microcrystalline cellulose, included from about 150 to about 210 g / l, particularly preferably at 180 g / l. Microcrystalline cellulose is considered not to be a hazardous substance under the European Community Directive67 / 548 / EEC. Cellulose levels of up to 300 g / l have been used, but blending becomes a pulp-like mixture, which creates problems in production using preferred equipment. Higher concentrations are thought to be feasible in using other manufacturing techniques to produce the indicator. An additional reducing agent is included, such as one or more reducing sugars. A preferred reducing sugar may be dextrose, although other reducing agents and sugars may be used. But, as previously described, in a preferred embodiment, reducing sugars that are approved food additives are used. For example, dextrose is a common ingredient used in infusion fluids. The concentration of dextrose must be adjusted as a function of the concentration of indigo carmine. It may be from about 1 to about 5 g / l of anhydrous dextrose, preferably from about 2 to about 4 g / l, particularly preferably from about 2.5 to about 4 g / l. Higher levels of dextrose lead to a decrease in the pH of the resulting mixture after sterilization, which has negative impacts on the functioning of the indicator.

In one embodiment of an indicator of the present invention, a carmine indigo mixture retains the yellow color and remains functional, that is, changes from yellow to blue under oxygen exposure after at least three months of storage at 40 ° C and particularly up to six months storage at 40 ° C. Moreover, when exposed to oxygen, the oxidized form retains the blue color for at least three months of storage at 40 ° C and particularly preferably up to six months of storage at 40 ° C.

In one embodiment, an indicator mixture is made by dissolving from about 14 to about 20 grams of carmine indigo in one liter of water. The water is preferably distilled. The mixture also includes from about 2.5 to about 4.0 grams / l of dextrose and from about 60 grams / l to about 75 grams / l of tetrasodium pyrophosphate. A thickener, which functions as a color intensifier and with a reducing capacity, is included in the mixture, such as microcrystalline cellulose, added at about 180 grams / l.

Example 2

A carmine indigo indicator mixture was made as follows:

14 g carmine indigo, 60 g tetrasodium pyrophosphate, 2.75 g anhydrous dextrose and 180 g microcrystalline cellulose were added to one liter of distilled water.

This mixture was placed in small pouches, which were loaded with oxygen absorber and placed in an outer oxygen-trap pouch and exposed to steam sterilization at 121 ° C. The samples were then stored in reduced form, and the reduced form, i.e. the yellow color of the indicator mixture was still yellow after storage in a substantially oxygen free environment for 112 days at 50 ° C.

When similar packages were exposed to oxygen, after first being put into a reduced state, as described above, the mixture changed to oxidized form, ie dark blue. The mixture remains dark blue after storage for 112 days at 50 ° C.

Example 3

A carmine indigo indicator mixture was made as follows:

60 g of tetrasodium pyrophosphate, 2.00 g of anhydrous dextrose and 180 g of microcrystalline cellulose were added to one liter of distilled water. The results were similar to those found in example 2 above.

Example 4

A 14 g / l carmine indigo solution was made to determine the degradation kinetics of blue color or oxidized form over a few months of storage. The indicator was made by mixing 14 g indigo car-mim, 60 g tetrasodium pyrophosphate, 2.5 g anhydrous dextrose and 180 g cellulose in one liter of distilled water.

Empty pouches with a nominal volume of 50 ml were filled with this 14 g / l indicator formulation, then wrapped in an outer bag with oxygen absorber and sterilized. During sterilization, the color of the indicator mixture changes from blue (oxidized form) to yellow (reduced form).

Then the outer pouch was perforated and the indicator mixture was reacted with atmospheric oxygen under ambient conditions. Then the color of the indicator mixture becomes blue again (oxidized form). Using a needle ring, 1.0 ml of indicator mixture was withdrawn through the medication port of the container. This aliquot was diluted to 50 ml with water and the cellulose was removed by filtration or centrifugation. Finally, 200 μl of the solution was loaded into a well of a polystyrene microtiter plate and absorption was recorded at 610 nm, ie the maximum wavelength at peak optical densities of the indigo car-mim in its oxidized form. A graph of optical densities (O.D.), measured from 350 to 750 nm, is shown in figure 13.

The test units were then stored at 25 ° C, 30 ° C and 40 ° C. Samples were taken at various time intervals and spectrophotometric measurements were made. The table below shows the results:

<table> table see original document page 56 </column> </row> <table>

Note: PO measurements are not available and therefore P15 measurements were recorded at PO

These data are inscribed on an exponential curve, which is shown in figure 14.

The values recorded up to 130 days indicate that the oxidized color is acceptable after 3 months at three temperatures and that the stability of oxidized blue sixesis can probably be achieved at the three storage temperatures.

Example 5

A carmine indigo indicator mixture was made as follows:

20 g of carmine indigo, 75 g of tetrasodium pyrophosphate, 4.0 g of anhydrous hexaphosphate and 180 g of microcrystalline cellulose were added to one liter of distilled water. This mixture was placed in small bags that were loaded with oxygen absorber and placed in an outer oxygen barrier bag and exposed to steam sterilization at 121 ° C. The samples were then stored in reduced form, and the reduced form, that is, the yellow color of the indicator mixture was still yellow after storage in a substantially oxygen free environment for 112 days at 50 ° C.

When similar packages were exposed to oxygen, after first being put into a reduced state, as described above, the mixture changed to oxidized form, ie dark blue. The mixture remains dark blue after storage for 112 days at 50 ° C.

An oxidized spectrographic analysis of this indicator mixture (20 g / l) was performed in the same manner as described with reference to the 14 g / l carmine indigo formulation and the results are shown in the table below:

<table> table see original document page 57 </column> </row> <table>

Results are also plotted in figure 15.

According to the absorption data, this 20 g / l formulation did not show oxidized color degradation after 124 days, but this may be due to detector saturation when absorption values approach 4 AU, together with some water loss. When samples are diluted 10-fold, a slight downward trend in absorption is observed at 40 ° C, but again the results indicate that the 6 month stability of the oxidized blue color at 40 ° C will be achieved with this formulation.

Example 6

Long-term stability states were then realized to show that the indicators work for the desired storage period of the products using the indicator. Two liters of an indicator containing 14 g / l indigo carmlm and an indicator formulation with 20 g / l indigo carmine were made to determine indicator activity and color degradation. The 14 g / l formulation was made by dissolving 120 g of sodium pyrophosphate in 2000 ml of water. To this solution were added 28 g of carmine indigo followed by 5 g of anhydrous dextrose. The solution was stirred for a few minutes to maximize dissolution of carmine indigo. Then, 360 g of cellulose was added. The pH has been measured but not adjusted. The pH must be above 9.4. The 20 g / l formulation was made by dissolving 150 g of sodium pyrophosphate in 2000 ml of water. To this solution was added 40 g of carmine indigo, followed by 8 g of anhydrous dextrose. The solution was stirred for a few minutes to maximize dissolution of carmine indigo. Then 360 g of cellulose was added. The pH was measured but not adjusted. The pH must be above 9.4.

A large number of small pouches were produced, which were filled with about 0.2 ml of the 14 g / l indicator formulation and the other half with the 20 g / l indicator formulation. These indicator pouches were then placed in separate outer pouches that contained multiple chamber water pouches. Half of the pouches containing 14 g / l indicators were thermally sterilized using a short thermal sterilization procedure, specifically 27 minutes of exposure at 121 ° C, to determine if the indicators would change shape oxidized (blue color). ) to the reduced form (yellow color), and the other half of the 14 g / l indicator was thermally sterilized using a long thermal sterilization procedure, specifically + 42 minutes exposure at122 ° C, to test the stability of both the reduced color and The same was done with the outer pouches containing the 20 g / l indicators.

Half of the samples or each batch were exposed to oxygen by puncturing the outer pouch using a 21G needle to create a micro-hole.

Then all the indicators in these exposed samples turned blue.

All samples were divided and stored in climate controlled rooms. One room was kept at 25 ° C and 40% relative humidity, a second room was kept at 30 ° C, 35% relative humidity, and a third room was kept at 40 ° C, 25% relative air humidity. These rooms were maintained under these conditions, with a tolerance of ± 2 ° C for temperature and ± 5% for relative humidity. Samples maintained at 40 ° C were tested at 0, 2, 4, 6 months and samples in the 25 ° C and 30 ° C rooms were tested at 0, 2, 4, 6, 9, 12, 15 months for each storage condition. Samples were visually inspected and categorized at the nearest Pantone® reference by means of the Pantone® Formulas Guide - coated in single color (second edition 2004) for each period and at each temperature. At each test period, a subset of the stored samples was selected from the exposed and unexposed lots of each room. The exposed lot indicator was examined to determine if the indicator still indicated the presence of oxygen showing a blue color. The unexposed samples were initially examined to determine if the indicator still indicated the absence of oxygen, then the outer pouch was punctured with the 21G needle to let oxygen enter the product enclosed by the outer pouch and the indicators were observed. with respect to a sufficient color change to show the presence of oxygen.

In summary, at 40 ° C and 6 months, all oxygen indicator samples worked as desired. All exposed samples continued to have a bluish color sufficient to indicate the presence of oxygen. All unexposed samples had a yellowish color to indicate the absence of oxygen. When the outer pouch was punctured, all unexposed samples now exposed changed to a bluish color sufficient to indicate the presence of oxygen. After 6 months, the tests at 40 ° C were completed.

Similar results were found in samples maintained at 25 ° C and 30 ° C at month 2, 3, 6, 9, 12, 15. Exposed samples continued to exhibit a color that indicated the presence of oxygen and the unexposed sample. continued to show a color that indicated the absence of oxygen, when the unexposed samples were then exposed to oxygen by puncturing the outer pouch with a needle, the samples changed color to indicate the presence of oxygen in the 67 hours.

The results are shown in figures 16, 17 and 18, which indicate the reduced color of the oxygen units, did not vary significantly after 6 months of storage under any of the storage conditions tested.

After sterilization, two units per formulation per sterilization cycle (8 units in total) were exposed to 2000 lux constant illumination with TL tube (day light) for 30 days at 25 ° C using a light box. Pantone® references are shown in Figure 20, which indicate that the formulations were not deteriorated by exposure to light.

A micro-hole was drilled into the outer bag, sweating a 21G needle from all units, including the illuminated units. All units turned blue after drilling within 1 to 67 hours. The nearest Pantone® reference was estimated at the temperature and period layer and the results for each temperature and period are shown in Figures 20, 21, 22, which indicate the oxidized color of oxygen units, did not vary significantly after 6 months of storage. , under any of the storage conditions tested.

From the foregoing, it can be seen that numerous variations and modifications can be made without departing from the spirit and scope of the invention. It is to be understood that no limitation is intended or deduced from the specific apparatus illustrated herein. Of course, it is intended to cover by the appended claims all modifications that fall within the scope of the claims.

Claims (10)

1. Flexible medical storage container comprising: a) a plurality of adjacent chambers, a first chamber positioned at one side end of the container, a second chamber positioned at an opposite side end of the chamber and at least one additional chamber positioned b) a first frangible barrier separating the first chamber at least one additional chamber and a second frangible barrier separating the second chamber from at least one additional chamber c) at least one window located at one end paincipient; each window providing fluid communication with a chamber different from the first, second and at least one additional chamber; and d) a longitudinal length of at least one additional chamber being substantially shorter than at least one of a longitudinal length of the first and second chambers. Flexible container according to claim 1, wherein the longitudinal length of at least one additional chamber is substantially smaller than the longitudinal length of both first and second chambers. Flexible container according to claim 1, wherein the longitudinal length of one of the first and second chambers is substantially less than the longitudinal length of at least one additional chamber. Flexible container according to claim 1, wherein the longitudinal length of one of the first and second chambers is equal to the longitudinal length of at least one additional chamber. Flexible container according to claim 1, wherein the container is in the form of a bag and is comprised of a multi-layer polymeric material. Flexible container according to claim 5, wherein the first and second frangible barriers are peelable seals. Flexible container according to claim 6 further including a suspending portion at an end opposite at least one window. Flexible container according to claim 7, further including three windows, each window providing fluid communication with a chamber different from the first, second and at least one additional chamber. Flexible container according to claim 8, wherein the suspending feature defines a higher edge of the first, second and at least one additional chamber. The flexible container of claim 9 further comprising a component of a restricted fluid parenteral patient formulation in each of the first, second and at least one additional chamber, wherein one of the components includes cysteine.